Genetic control of the antibody and T-cell proliferative responses of mice to the natural protein antigens staphylococcal nuclease and sperm whale myoglobin has been studied. H-2 linked control of the response to nuclease has been shown to be exerted at the level of individual determinants independently of one another, rather than the molecule as a whole, by comparing the specificity of antibodies made to nuclease by two different pairs of congenic mice, each differing only at H-2. T-cell proliferative studies have suggested the existence of more than one H-2-linked Ir gene controlling the response to the several determinants. In addition, a non-H-2 linked gene(s) was demonstrated to control the overall level of response to the whole molecule, and was shown to be unlinked to heavy chain allotype and sex as well. Finally, the antibody response to myoglobin was demonstrated to be under control of at least two genes mapping in different Ir subregions of the H-2 complex, as well as at least one non-H-2 linked gene. BIBLIOGRAPHIC REFERENCES: Berzofsky, J.A., Schechter, A.N., Shearer, G.M., and Sachs, D.H.: Genetic control of the immune response to staphylococcal nuclease III. Time course and correlation between the response to native nuclease and the response to its polypeptide fragments. J. Exp. Med. 145:111-122, 1977. Berzofsky, J.A., Schechter, A.N., Shearer, G.M., and Sachs, D.H.: Genetic control of the immune response to staphylococcal nuclease IV. H-2-linked control of the relative proportions of antibodies produced to different determinants of native nuclease. J. Exp. Med. 145:123-135, 1977.